Dermal anti-inflammatory composition

Abstract

A pharmaceutical composition for dermal application comprises a lipophilic anti-inflammatory compound and a pharmaceutically acceptable vehicle comprising a lipophilic excipient capable of solubilizing the anti-inflammatory compound and targeting said compound to the pilosebaceous ducts on application of the composition on the skin. The composition may be used in the treatment of dermal inflammatory conditions, in particular acne.

1 . A pharmaceutical composition for dermal application comprising a lipophilic anti-inflammatory compound and a pharmaceutically acceptable vehicle comprising a lipophilic excipient capable of solubilising the anti-inflammatory compound and targeting said compound to the pilosebaceous ducts on application of the composition to the skin.  
     
     
         2 . A composition according to  claim 1 , wherein the lipophilic excipient has a viscosity in the range of from about 2 to about 200 mpa.s.  
     
     
         3 . A composition according to  claim 2 , wherein the lipophilic excipient further has a polarity similar to that of sebum.  
     
     
         4 . A composition according to any of of claims  1 - 3 , wherein the lipophilic excipient has a Hildebrand coefficient of about 7.5-8.0±2 (cal/cm 3 ) ½ .  
     
     
         5 . A composition according to any one of claims  1 - 4 , wherein the lipophilic excipient comprises a mono-, di- or triglyceride of a C 6-12  carboxylic acid, or a vegetable oil such as fractionated coconut oil.  
     
     
         6 . A composition according to  claim 5 , wherein the lipophilic excipient comprises a glyceride of a C 8-10  carboxylic acid.  
     
     
         7 . A composition according to  claim 6 , wherein the lipophilic excipient comprises a glyceride of a C 8-10  carboxylic acid conjugated with polyalkylene glycol, in particular polyethylene glycol.  
     
     
         8 . A composition according to  claim 5 , wherein the lipophilic excipient is selected from the group consisting of PEG-6 caprylic/capric glycerides or mixtures thereof, or PEG-8 caprylic/capric glycerides or mixtures thereof.  
     
     
         9 . A composition according to any of claims  1 - 8 , wherein the vehicle additionally comprises a solvent selected from the group consisting of water, an alcohol or mixtures thereof.  
     
     
         10 . A composition according to  claim 9 , wherein the alcohol is ethanol, propanol or isopropanol.  
     
     
         11 . A composition according to any of claims  1 - 10 , wherein the anti-inflammatory compound is one which, in addition to exhibiting an anti-inflammatory activity, exhibits a comedolytic activity.  
     
     
         12 . A composition according to any of claims  1 - 11 , wherein the anti-inflammatory compound has the general formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  represents 1-5 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, C 1-6  alkyl, C 1-6  alkylthio, C 1-6  alkylamino, C 1-6  alkoxy, C 1-6  alkoxycarbonyl, cyano, carbamoyl, phenyl and nitro;  
 R 2  represents 1-4 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, carboxy, mercapto, trifluoromethyl, amino, C 1-6  alkyl, C 1-6  alkylthio, C 1-6  alkylamino, C 1-6  alkoxy, C 1-6  alkoxycarbonyl, cyano, carbamoyl, phenyl and nitro;  
 R 3  represents 1-4 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, C 1-6  alkyl, C 1-6  alkylthio, C 1-6  alkylamino, C 1-6  alkoxy, C 1-6  alkoxycarbonyl, cyano, carbamoyl, phenyl and carboxy;  
 R 4 , R 5  and R 6  are independently hydrogen, trifluoromethyl, C 1-6  alkyl, carbamoyl, C 1-6  alkoxycarbonyl or C 1-6  alkanoyl;  
 X is O, S, N—OH or N—O—C 1-6  alkyl;  
 and salts thereof with pharmaceutically acceptable acids, hydrates and solvates,  
 with the proviso that when the compound of formula I is 4-(2-amino-4-bromophenylamino)-2-chloro-2′-methylbenzophenone, the lipophilic excipient is not PEG-8 caprylic/capric triglyceride.  
 
     
     
         13 . A composition according to  claim 12 , wherein 
 each R 1  is independently halogen, hydroxy, C 1-6  alkyl, C 1-6  alkylthio, C 1-6  alkoxy or cyano;    each R 2  is independently halogen, hydroxy, C 1-6  alkyl, C 1-6  alkylthio, C 1-6  alkoxy or cyano;    each R 3  is independently halogen, hydroxy, mercapto, trifluoromethyl, C 1-6  alkyl, C 1-6  alkylthio, C 1-6  alkoxy or cyano;    R 4  and R 5  are both hydrogen, R 6  is hydrogen or methyl; and    X is O.    
     
     
         14 . A composition according to  claim 13 , wherein the anti-inflammatory compound is selected from the group consisting of 
 4-(2-Amino-4-bromophenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Amino-4-fluorophenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Aminophenylamino)-2,2′-dichloro-4′-methoxybenzophenone,    4′-(2-Aminophenylamino)-2,2′,3-trichloro-4-methoxybenzophenone,    4′-(2-Aminophenylamino)-2,2′,6-trichloro-4-methoxybenzophenone,    4-(2-Aminophenylamino)-2-choro-2′-hydroxybenzophenone,    4-(2-Aminophenylamino)-2-chloro-2′-fluorobenzophenone,    4-(2-Aminophenylamino)-2,2′-dichloro-4′-hydroxybenzophenone,    4-(2-Amino-4-bromophenylamino)-2-chloro-4′-ethoxy-2′-methylbenzophenone,    4-(2-Amino-4-bromophenylamino)-2-ethoxy-2′-methylbenzophenone,    4′-(2-Aminophenylamino)-2,2′,4-trichloro-6-hydroxybenzophenone,    4-(2-Amino-5-hydroxyphenylamino)-2-chloro -2′-methylbenzophenone,    4-(2-Aminophenylamino)-2-fluoro-2′-methoxybenzophenone,    4-(2-Aminophenylamino)-2-fluoro-2′-methylbenzophenone,    4-(2-Amino-5-methoxyphenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Amino-5-chlorophenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Amino-4-(trifluoromethyl)phenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Amino-3-fluorophenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Amino-N-methyl-phenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Aminophenylamino)-2,2′-dimethylbenzophenone,    4-(2-Amino-4-fluoro-N-methyl-phenylamino)-2chloro-2′-methylbenzophenone,    4-(2-Amino-6-methylphenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Amino-4-methoxyphenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Aminohenylamino)-2-chloro-3′-fluoro-2′-methylbenzophenone,    4-(2-Amino-4-bromophenylamino)-2-chloro-2′,3′-dimethylbenzophenone,    4-(2-Amino-4-bromophenylamino)-4′-n-butyl-2-chloro-2′-methylbenzophenone,    4-(2-Amino-4-bromophenylamino)-2,4′-dichloro-2′-methylbenzophenone,    4-(2-Amino-4-bromophenylamino)-2-fluoro-2′-methylbenzophenone,    4′-(2-Amino-4-bromophenylamino)-2′-chloro-2,4,5-trimethylbenzophenone,    4-(2-Amino-4-bromophenylamino)-2-chloro-4′-fluoro-2′-methylbenzophenone,    4-(2-Amino-4-bromophenylamino)-2-chloro-2′,5′-dimethylbenzophenone,    4-(2-Amino-4-bromophenylamino)-2,3′-dichloro-2′-methylbenzophenone,    4-(2-Amino-4-bromophenylamino)-2-fluoro-4′-methoxy-2′-methylbenzophenone,    and their salts with pharmaceutically acceptable acids, their hydrates, or solvates.    
     
     
         15 . A composition according to any of claims  1 - 11 , wherein the anti-inflammatory compound has the general formula II  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is halogen, hydroxy, mercapto, trifluoromethyl, amino, C 1-3  alkyl, C 1-3  alkylthio, C 1-3  alkylamino, C 1-3  alkoxy, C 1-3  alkoxycarbonyl, C 2-3  olefinic group, cyano, —CONH 2 , phenyl or nitro;  
 R 2  represents 1-4 substituents independently selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino, C 1-3  alkyl, C 1-3  alkylthio, C 1-3  alkylamino, C 1-3  alkoxy, C 1-3  alkoxycarbonyl, C 2-3  olefinic group, cyano, —CONH 2 , phenyl and nitro;  
 R 3  represents 1-5 substituents independently selected from the group consisting of halogen, hydroxy, mercapto, trifluoromethyl, amino, carboxy, carbamoyl, C 1-10  alkyl, C 1-10  alkylthio, C 1-10  alkoxy, C 1-10  alkoxycarbonyl, C 2-10  olefinic group, C 3-8  monocyclic hydrocarbon group, cyano and phenyl;  
 R 6  is hydrogen, C 1-6  alkyl, C 2-6  olefinic group, C 3-6  monocyclic hydrocarbon group;  
 R 7  represents 1-4 substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, mercapto, trifluoromethyl, amino, C 1-3  alkyl, C 1-3  alkylthio, C 1-3  alkylamino, C 1-3  alkoxy, C 1-3  alkoxycarbonyl, C 2-3  olefinic group, cyano, —CONH 2 , phenyl or nitro;  
 X is O, S or N—OH;  
 and salts thereof with pharmaceutically acceptable acids, hydrates or solvates.  
 
     
     
         16 . A composition according to  claim 15 , wherein R 1  is fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C 1 -C 2 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )alkoxycarbonyl, cyano, and —CONH 2 , in particular fluoro, chloro, bromo, hydroxy, methyl, or methoxy.  
     
     
         17 . A composition according to  claim 15 , wherein each R 2  is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, and (C 1 -C 3 )alkoxy, in particular hydrogen, fluoro, chloro, bromo, hydroxy, methyl, and methoxy.  
     
     
         18 . A composition according to  claim 15 , wherein each R 3  is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkoxycarbonyl, cyano, carboxy, and —CONH 2 , in particular hydrogen, fluoro, chloro, bromo, hydroxy, methyl, methoxy, cyano, and carboxy.  
     
     
         19 . A composition according to  claim 15 , wherein R 6  represents hydrogen, (C 1 -C 4 )alkyl, or (C 2 -C 4 )olefinic group, in particular hydrogen, methyl, or ethyl.  
     
     
         20 . A composition according to  claim 15 , wherein X represents oxygen or sulphur, in particular oxygen.  
     
     
         21 . A composition according to  claim 15 , wherein each R 7  is selected from the group consisting of hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, amino, (C 1 -C 2 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )alkoxycarbonyl, cyano, and —CONH 2 , in particular hydrogen, fluoro, chloro, bromo, hydroxy, trifluoromethyl, methyl, ethyl, and methoxy.  
     
     
         22 . A composition according to any of claims  15 - 21 , wherein the anti-inflammatory compound is selected from the group consisting of 
 2-[[3-Chloro-4-(2-methylbenzoyl)]phenylamino]benzonitrile,    2-Chloro-2′-methyl-4-(2-methyl-phenylamino)benzophenone,    2-Chloro-2′-methyl-4-(phenylamino)benzophenone,    2-Chloro-4-(2-methoxy-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(2-fluoro-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(2-chloro-phenylamino)-2′-methylbenzophenone,    4-(2-tert-Butoxy-phenylamino)-2-chloro-2′-methylbenzophenone,    2-Chloro-4-(2-hydroxy-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(3-chloro-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(2-[1,1,1-trifluoromethyl]-phenylamino)-2′-methylbenzophenone,    4-(4-Bromo-2,5-difluoro-phenylamino)-2-chloro-2′-methylbenzophenone,    2-Chloro-4-(2-ethyl-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(3-[1,1,1-trifluoromethyl]phenylamino)-2′-methylbenzophenone,    2-Chloro-2′-methyl-4-(2-phenyl-phenylamino)benzophenone,    2-Chloro-2′-methyl-4-(3-phenyl-phenylamino)benzophenone,    2-Chloro-4-(4-fluoro-2-methyl-phenylamino)-2′-methylbenzophenone,    2-Chloro-2′-methyl-4-(3-methyl-phenylamino)benzophenone,    2-Chloro-4-(3-methoxy-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(4-chloro-phenylamino)-2′-methylbenzophenone,    2-Chloro-2′-methyl-4-(4-phenyl-phenylamino)benzophenone,    4-(4-Bromo-phenylamino)-2-chloro-2′-methylbenzophenone,    4-(4-Bromo-3-fluoro-phenylamino)-2-chloro-2′-methylbenzophenone,    4-(2-Bromo-phenylamino)-2-chloro-2′-methylbenzophenone,    2-Chloro-4-(4-chloro-2-methyl-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(4-chloro-3-fluoro-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(3-fluoro-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(3,5-difluoro-phenylamino)-2′-methylbenzophenone,    4-(3-Bromo-phenylamino)-2-chloro-2′-methylbenzophenone,    2-Chloro-4-(3,4-difluoro-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(5-fluoro-2-methyl-phenylamino)-2′-methylbenzophenone,    2-Chloro-4-(3-fluoro-2-methyl-phenylamino)-2′-methylbenzophenone,    Ethyl 2-[[3-chloro-4-(2-methylbenzoyl)]phenylamino]benzoate,    2-Chloro-3′-fluoro-4-(4-fluoro-2-methyl-phenylamino)-2′-methylbenzophenone,    2-[[3-Chloro-4-(2-methylbenzoyl)]phenylamino]benzoic acid,    and salts thereof with pharmaceutically acceptable acids, hydrates and solvates.    
     
     
         23 . A composition according to any of claims  1 - 22 , wherein the vehicle additionally comprises a penetration enhancer.  
     
     
         24 . A composition according to  claim 23 , wherein the penetration enhancer is selected from the goup consisting of propylene glycol mono- or diesters of C 2-20  carboxylic acids or C 4-16  alkyl esters.  
     
     
         25 . A composition according to  claim 24 , wherein the penetration enhancer is selected from the group consisting of propylene glycol octanoate, propylene glycol decanoate, propylene glycol dipelargonate, propylene glycol monolaurate, propylene glycol monomyristate, propylene glycol dicaprylate, diethyl adipate, dicapryl adipate, diisopropyl adipate, dipropyl adipate, dioctyl adipate and dibutyl adipate.  
     
     
         26 . A composition according to any of claims  1 - 25 , wherein the vehicle comprises 
 (a) a lipophilic excipient in an amount of about 10-80% w/w,    (b) an alcohol in an amount of about 0-80% w/w,    (c) water in an amount of about 0-50% w/w,    (d) a penetration enhancer in an amount of about 0-15% w/w,    (e) a thickening agent in an amount of about 0-15% w/w,    (f) a surfactant in an amount of about 0-5% w/w.    
     
     
         27 . A composition according to  claim 26 , wherein the amount of active substance is in the range of from about 0.5 to about 5% w/v, preferably from about 1 to about 4.5% w/v, more preferably from about 2 to about 4% w/v, such as about 3% w/v, relative to the amount of vehicle.  
     
     
         28 . Use of a pharmaceutical composition comprising a lipophilic anti-inflammatory compound and a pharmaceutically acceptable vehicle comprising a lipophilic excipient capable of solubilising the anti-inflammatory compound and targeting said compound to the pilosebaceous ducts of the skin on application for the manufacture of a medicament intended for dermal application for the prevention or treatment of local inflammatory conditions of the skin.  
     
     
         29 . The use of  claim 28 , wherein the inflammatory condition is contact dermatitis, atopic dermatitis, eczema or acne.  
     
     
         30 . Use of a pharmaceutical composition according to any of claims  1 - 27  for the manufacture of a medicament for exerting a comedolytic activity when applied on skin.  
     
     
         31 . A method of preventing or treating dermal inflammatory conditions, the method comprising dermally applying at or on a site of inflammation a sufficient quantity of a pharmaceutical composition comprising a lipophilic anti-inflammatory compound and a pharmaceutically acceptable vehicle comprising a lipophilic excipient capable of solubilising the anti-inflammatory compound and targeting said compound to the pilosebaceous ducts of the skin on application.  
     
     
         32 . The method of claim  34 , wherein the inflammatory condition is contact dermatitis, atopic dermatitis, eczema or acne.